For the purpose of the academic understanding of atopic diseases and the improvement and the treatment of their symptoms, there are many attempts by researchers to understand the immunoregulatory mechanisms in a living body or the cell signaling mechanisms and the methods employing the mechanisms along with the development of immunology and cytology. On the other hand, some studies have been going on by some researchers to elucidate the causes of the diseases on the changes with the development of modern civilization, that is, the changes in diet or the exposure to pollutants.
The common fact found in the studies on the atopic diseases in these various findings is that the serum proteins exude from skin or mucosa of patients with atopic diseases, regardless of the understanding that the atopic diseases would be caused by the immunological reasons. However, there has been no study to conclude clearly whether the serum proteins exude from the skin or mucosa as a result of the development of the atopic diseases or the exudation of the serum proteins in the skin or mucosa triggers the atopic diseases.
It is known that the exudation of the serum proteins in outer skin or mucosa are observed mainly using serum albumin as a marker protein. It has been known that an exudation level of serum albumin in the skin diseases is closely correlated with the severity of the diseases. Hypoalbuminemia in the blood is induced as the serum proteins severely exuded from the skin (Worm et al., 1981. Br. J. Dermatol. 104: 389-396; and Worm and Rossing, 1980. J. Invest. Dermatol. 75: 302-305). Patients are suffering from allergic asthma and rhinitis developed symptoms such as intestinal lymphangiectasia that resulted by severe loss of albumin through the inner wall of the intestines (Esenberh, 1976. Ann. Allergy, 36: 342-350). In case of children, the loss of albumin by severe skin diseases makes them retard their growth (Abrahamov, 1986. Eur. J. Pediatr. 145: 223-226), and is also accompanied with oiguria and acrocyanosis along with the lymphangiectasia (Capulong et al. 1996. Pediatr. Allergy Immunol. 7: 100-102). It was reported that an exudation level of albumin in diseased skin area is closely related to the severity of the conditions even in the case of atopic eczema and contact dermatitis (David et al., 1990. Br. J. Dermatol. 122: 485-489; and Wijsbek et al., 1991. Int. J. Microcirc. Clin. Exp. 10: 193-204).
It was reported that the exudation of albumin-including serum proteins was found even in sputa of the patients suffering from symptoms of asthma and chronic obstructive pulmonary disease (Schoonbrood et al. 1994. Am. J. Respir. Crit. Care Med. 150:1519-1527; and Anderson & Persson 1988. Agents Actions Suppl. 23: 239-260), and it was also reported that the exudation of albumin occurs without a sign of eosinophilia in the case of chronic cough (Pizzichini et al., 1999. Can. Respir. J. 6:323-330).
The exudation of the serum proteins is induced by the chemicals including materials such as methyl salicylate, phenol, croton oil, benzalkonium, etc. (Patrick et al. 1985. Toxicol. Appl. Pharmacol. 81: 476-490); and toluene, m-xylene, cyclohexane, etc. (Iyadomi et al., 1998. Ind. Health 36:40-51). 2,4-dinitrofluorobenzne is used in the animal models to conduct a skin irritation study, and also induces the exudation of the serum proteins (Nakamura et al., 2001. Toxical. Pathol. 29:200-207). It was reported that all organic solvent materials do not induce the exudation of the serum proteins, and the exudation levels are also varied according to the structure of chemicals. The exudation of the serum proteins is easily induced by the chemicals having aromatic rings, but nearly affected by organic solvents such as acetone.
Keeping in mind that the atopic diseases are caused by reason of the westernized food habits (Weiland et al., 1999. Lancet 353:2040-2041; von Mutis et al., 1998. Lancet 351:862-866; and Dunder et al., 2001. Allergy 56:425-428), the researchers have paid attention to the changes of the components and the content of lipids ingested by the people. With the advent of 1970s, a few of researchers have found that the imbalance of the human metabolism is caused by the excessive ingestion of unsaturated fatty acid and trans oil which are main components of vegetable oil, which results in the augmentation of the atopic diseases.
Unlike other tissues and organs, there are various phospholipids having a very high content of di-saturated fatty acids in lungs of mammals including human, and the surfactant present on the surface of lung have, in particular, a very high content of dipalmitoylphosphatidylcholine (DPPC). It has been known that the component functions to reduce a surface tension in lungs. The reduction of the surface tension by the surfactant on the surface of lung can be made easy to breathe when air is inhaled into the lungs, and prevents alveolar walls from being attached to each other or their structure from being collapsed when exhaled out. The lipid component of the surfactant is composed of about 90% of phospholipid (about 70% of the phospholipid is di-saturated phospholipid), and about 10% of neutral fat (a majority of the neutral fat is cholesterol) (Reviews: Jon Goerke 1998. Biochem. Biophy. Acta. 1408:79-89; and Veldhuizen et al., 1998. Biochim. Biophys. Acta. 90-108).
One of the scientific results that should be further considered in addition to the facts as described above is a pathway for synthesizing the surfactant lipids in the lungs. One point is that most cholesterol present in the human lung is supplied from the blood. Cholesterol synthesized in the lung accounts for only about 1%, and the rest of cholesterol should be supplied from the blood (Hass and Longmore, 1979. Biochim. Biophys. Acta 573:166-174). It has been known that phospholipids constituting most of the surfactant of the lung are synthesized in and secreted from Type II epithelial cells, but most of the fatty acid constituting the phospholipids are supplied from VLDL (very low density lipoprotein) in the blood (Rama et al., 1997. J. Clin. Invest. 99: 2020-2029).
SP-A (surfactant protein A) is one of the major proteins present in the surfactant in lung that has been studied for the last 30 years. The SP-A protein is synthesized in and secreted from Type II epithelial cells present in the alveoli, and also found in a surface of the small intestine, Eustachian tube of ear, tears, etc. Its molecular weight is approximately 700 kDa (measured by a gel-filtration assay), and its 18 identical units, each having a molecular weight of 32 kDa, are gathered to form a mature protein having the peculiar function. It has been known that the protein has various biological functions, but they may be mainly categorized into two groups. The first is an immunological function in which SP-A protects the lungs by binding to bacteria or viruses, as well as a house dust mite, anther dust, etc. which enter the lungs while breathing in. The second function is taking part in maintaining the homeostasis of the surfactant in lung (Tino and Wright 1998. Biochim. Biophys. Acta. 1408: 241-263; Haagsman, Biochim. Biophys. Acta. 1408: 264-277; Crouch & Wright, 2001. Annu. Rev. Physiol. 63:521-524; and Haagsman and Diemel, 2001 Compar. Biochem. Physiol. 129: 191-108).